1. Field of the Invention
The invention relates to a process for the preparation of dialkyl alkoxyalkylidenemalonates by reaction of malonic acid esters with trialkyl orthocarboxylates. Alkoxyalkylidenemalonic malonic acid esters are important intermediates for the synthesis of various substituted quinolines which are employed as pharmaceuticals against malaria or bacterial infections.
2. Discussion of the Background
The preparation of the alkoxyalkylidenemalonic acid esters from malonic acid esters and orthocarboxylic acid esters is known. The condensation is carried out in acetic anhydride using ZnCl.sub.2 as catalyst according to L. Claisen, Berichte 26, 2729 (1893).
Since then, various improvements to this route of preparation have been put forward with the aim of increasing the yields and the productivity of the reaction.
According to DE 2,426,964, the reaction of dialkyl malonate with an excess of trialkyl orthoformate is carried out in the presence of sub-stoichiometric amounts of acetic anhydride and Lewis acids such as zinc salts, aluminum salts or iron salts as catalyst For the preparation of diethyl ethoxymethylenemalonate, a yield of 94% of the theoretical yield based on malonic ester is mentioned. The preparation of dimethyl methoxymethylenemalonate is carried out under analogous conditions with a yield of 70% of the theoretical yield and, at a pressure of 3 bar, with a yield of 86% based on the malonic acid ester. These yields are not satisfactory. As a result of the incomplete conversion, purities of only 94 are obtained.
If, as described in U.S. Pat. No. 2,824,121, the preparation of diethyl ethoxymethylenemalonate is carried out by reaction of diethyl malonate with triethyl orthoformate in the absence of Lewis acids using acetic acid as the only catalyst, a yield of 91.8%, based on reacted diethyl malonate, with a conversion of only 60%, is achieved.
In EP 0,152,319, the reaction of diethyl malonate with triethyl orthoformate is catalysed by salts of Cd, Hg, Bi and Mg. The yields of diethyl ethoxymethylenemalonate determined by gas chromatography are very high. However, they do not correspond to the yields practically attainable by isolation of the product.
The Cd, Hg and Bi salts additionally lead to heavy metal-containing product residues. The disposal of these residues is increasingly difficult and cost-intensive. Also, from ecological points of view, a substitution of the metal salts appears desirable. The contamination of the alkoxyalkylidenemalonic esters with such toxic metal salts may limit their use as pharmaceutical precursors or even make it impossible.
The known catalysts moreover yield dimethyl methoxymethylenemalonate in unsatisfactory yields in the reaction of the less active trimethyl orthoformate with dimethyl malonate.